The research proposed in this application deals with theoretical and experimental studies toward four major objectives: The first objective is to determine the mechanisms of synchronous firing of pacemaker cells in the sinoatrial (SA) node, and to provide an accurate description of the manner in which local circuit currents control synchronization. Measurements using rabbit SA node tissue will be obtained by superfusion with chemicals that change cell-to-cell coupling, membrane resistance and excitability. Synchronization and intercellular coupling will be studied also using pairs of single SA cells and cell clusters, and in computer simulations using a set of theoretical models of pacemaker activity of the Hodgkin-Huxley type. These studies should help us to predict quantitatively the manner in which thousands of SA node cells initiate the heart beat. The second objective is to expand our studies on the autonomic regulation of heart rate, rhythm and conduction. Specifically, the mechanism of the secondary inhibitory component of the triphasic response of heart rate to brief vagal volleys will be studied in isolated rabbit SA node preparations, and in computer simulations. In addition, we will use isolated SA node preparations, single cells and computer modeling to investigate the cellular basis of the fade in the hyperpolarizing response of SA and AV nodes to continuous vagal stimulation. The third objective is to study the role of passive membrane properties in the conduction of impulses across nonhomogeneous tissues. In sheep and dog Purkinje fibers, we will determine the effects of segmental changes in excitability, membrane resistance and intercellular resistance on propagation velocity, and will estimate the potential arrhythmogenicity of these changes. Finally, we will extend our observations on drug-induced automaticity in ventricular muscle. Specific attention will be given to the spontaneous activity that can be induced at relatively high (-80 to -95 mV) membrane potentials, and to the possible coexistence of this activity with early afterdepolarizations originating at less negative (-40 to -65) levels of potential.